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ACERYCAL 10MG/10MG TABLET

Active substance(s): AMLODIPINE BESILATE / PERINDOPRIL ARGININE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
ACERYCAL 10mg/10mg tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
One tablet contains 6.790 mg perindopril equivalent to 10 mg perindopril
arginine and 13.870 mg amlodipine besilate equivalent to 10 mg amlodipine.
Excipient : lactose monohydrate.
For a full list of excipients, see 6.1.

3

PHARMACEUTICAL FORM
Tablet.
White, round tablet engraved with 10/10 on one face and
face.

on the other

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
ACERYCAL is indicated as substitution therapy for treatment of essential
hypertension and/or stable coronary artery disease, in patients already
controlled with perindopril and amlodipine given concurrently at the same
dose level.

4.2

Posology and method of administration
Oral route.
One tablet per day as a single dose, preferably to be taken in the morning and before a
meal.
The fixed dose combination is not suitable for initial therapy.
If a change of posology is required, the dose of ACERYCAL could be modified or
individual titration with free combination may be considered.
Special populations
Patients with renal impairment and elderly (see sections 4.4 and 5.2)
Elimination of perindoprilat is decreased in the elderly and in patients with renal
failure. Therefore, the usual medical follow-up will include frequent monitoring of
creatinine and potassium.
ACERYCAL can be administered in patients with Clcr ≥ 60ml/min, and is not
suitable for patients with Clcr < 60ml/min. In these patients, an individual dose
titration with the mono-components is recommended.

Amlodipine used at similar doses in elderly or younger patients is equally well
tolerated. Normal dosage regimens are recommended in the elderly, but increase of
the dosage should take place with care. Changes in amlodipine plasma concentrations
are not correlated with degree of renal impairment. Amlodipine is not dialysable.
Patients with hepatic impairment: see sections 4.4 and 5.2
Dosage recommendations have not been established in patients with mild to moderate
hepatic impairment; therefore dose selection should be cautious and should start at the
lower end of the dosing range (see sections 4.4 and 5.2). To find the optimal starting
dose and maintenance dose of patients with hepatic impairment, the patients should
be individually titrated using the free combination of amlodipine and perindopril. The
pharmacokinetics of amlodipine have not been studied in severe hepatic impairment.
Amlodipine should be initiated at the lowest dose and titrated slowly in patients with
severe hepatic impairment.
Paediatric populations
ACERYCAL should not be used in children and adolescents as the efficacy and
tolerability of perindopril and amlodipine, in combination, have not been established
in children and adolescents.

4.3

4.4

Contraindications

-

Linked to perindopril:
Hypersensitivity to perindopril or to any other ACE inhibitor,

-

History of angioedema associated with previous ACE inhibitor therapy,

-

Hereditary or idiopathic angioedema,

-

Second and third trimesters of pregnancy (see sections 4.4 and 4.6),

-

Concomitant use of ACERYCAL with aliskiren-containing products in patients with
diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²) (see sections 4.5
and 5.1).

-

Linked to amlodipine:
Severe hypotension,

-

Hypersensitivity to amlodipine or to dihydropyridines derivatives,

-

Shock, including cardiogenic shock,

-

Obstruction of the outflow-tract of the left ventricle (e.g. high grade aortic stenosis),

-

Haemodynamically unstable heart failure after acute myocardial infarction.

-

Linked to ACERYCAL:
All contraindications related to each mono-component, as listed above, should apply
also to the fixed combination of ACERYCAL.
Hypersensitivity to any of the excipients.

Special warnings and precautions for use

All warnings related to each mono-component, as listed below, should apply also to the fixed
combination of ACERYCAL.
Linked to perindopril
Special warnings
Hypersensitivity/Angioedema:
Angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx
has been reported rarely in patients treated with ACE inhibitors, including perindopril (see
section 4.8). This may occur at any time during therapy. In such cases, ACERYCAL should
promptly be discontinued and appropriate monitoring should be initiated and continued until
complete resolution of symptoms has occurred. In those instances where swelling was
confined to the face and lips the condition generally resolved without treatment, although
antihistamines have been useful in relieving symptoms.
Angioedema associated with laryngeal oedema may be fatal. Where there is involvement of
the tongue, glottis or larynx, likely to cause airway obstruction, emergency therapy should be
administered promptly. This may include the administration of adrenaline and/or the
maintenance of a patent airway. The patient should be under close medical supervision until
complete and sustained resolution of symptoms has occurred.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased
risk of angioedema while receiving an ACE inhibitor (see section 4.3).
Intestinal angioedema has been reported rarely in patients treated with ACE inhibitors. These
patients presented with abdominal pain (with or without nausea or vomiting); in some cases
there was no prior facial angioedema and C-1 esterase levels were normal. The angioedema
was diagnosed by procedures including abdominal CT scan, or ultrasound or at surgery and
symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be
included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal
pain (see section 4.8).
Anaphylactoid reactions during low-density lipoproteins (LDL) apheresis:
Rarely, patients receiving ACE inhibitors during low-density lipoprotein (LDL) apheresis
with dextran sulfate have experienced life-threatening anaphylactoid reactions. These
reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each
apheresis.
Anaphylactoid reactions during desensitisation:
Patients receiving ACE inhibitors during desensitisation treatment (e.g. hymenoptera venom)
have experienced anaphylactoid reactions. In the same patients, these reactions have been
avoided when the ACE inhibitors were temporarily withheld, but they reappeared upon
inadvertent rechallenge.
Neutropenia/Agranulocytosis/Thrombocytopenia/Anaemia:
Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients
receiving ACE inhibitors. In patients with normal renal function and no other complicating
factors, neutropenia occurs rarely. Perindopril should be used with extreme caution in patients
with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or
procainamide, or a combination of these complicating factors, especially if there is preexisting impaired renal function. Some of these patients developed serious infections, which
in a few instances did not respond to intensive antibiotic therapy. If perindopril is used in such
patients, periodic monitoring of white blood cell counts is advised and patients should be
instructed to report any sign of infection (e.g. sore throat, fever).

Dual blockade of the renin-angiotensin-aldosterone system (RAAS):
There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers
or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function
(including acute renal failure). Dual blockade of RAAS through the combined use of ACEinhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see
sections 4.5 and 5.1).
If dual blockade therapy is considered absolutely necessary, this should only occur under
specialist supervision and subject to frequent close monitoring of renal function, electrolytes
and blood pressure.
ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in
patients with diabetic nephropathy.

Pregnancy
ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitors is
considered essential, patients planning pregnancy should be changed to alternative
antihypertensive treatments which have an established safety profile for use in pregnancy.
When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately,
and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
Precautions for use
Hypotension:
ACE inhibitors may cause a fall in blood pressure. Symptomatic hypotension is seen rarely in
uncomplicated hypertensive patients and is more likely to occur in patients who have been
volume-depleted e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or
vomiting, or who have severe renin-dependent hypertension (see sections 4.5 and 4.8). In
patients at high risk of symptomatic hypotension, blood pressure, renal function and serum
potassium should be monitored closely during treatment with ACERYCAL.
Similar considerations apply to patients with ischaemic heart or cerebrovascular disease in
whom an excessive fall in blood pressure could result in a myocardial infarction or
cerebrovascular accident.
If hypotension occurs, the patient should be placed in the supine position and, if necessary,
should receive an intravenous infusion of sodium chloride 9 mg/ml (0.9%) solution. A
transient hypotensive response is not a contraindication to further doses, which can be given
usually without difficulty once the blood pressure has increased after volume expansion.
Aortic and mitral valve stenosis / hypertrophic cardiomyopathy:
As with other ACE inhibitors, perindopril should be given with caution to patients with mitral
valve stenosis and obstruction in the outflow of the left ventricle such as aortic stenosis or
hypertrophic cardiomyopathy.
Renal impairment:
In cases of renal impairment (creatinine clearance < 60 ml/min) an individual dose titration
with the mono-components is recommended (see section 4.2).
Routine monitoring of potassium and creatinine are part of normal medical practice for
patients with renal impairment (see section 4.8).
In some patients with bilateral renal artery stenosis or stenosis of the artery to a solitary
kidney, who have been treated with ACE inhibitors, increases in blood urea and serum
creatinine, usually reversible upon discontinuation of therapy, have been seen. This is
especially likely in patients with renal insufficiency. If renovascular hypertension is also
present there is an increased risk of severe hypotension and renal insufficiency. Some
hypertensive patients with no apparent pre-existing renal vascular disease have developed

increases in blood urea and serum creatinine, usually minor and transient, especially when
perindopril has been given concomitantly with a diuretic. This is more likely to occur in
patients with pre-existing renal impairment.
Hepatic failure:
Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic
jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism
of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice
or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive
appropriate medical follow-up (see section 4.8).
Race:
ACE inhibitors cause a higher rate of angioedema in black patients than in non-black patients.
As with other ACE inhibitors, perindopril may be less effective in lowering blood pressure in
black people than in non-blacks, possibly because of a higher prevalence of low-renin states
in the black hypertensive population.
Cough:
Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is nonproductive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced
cough should be considered as part of the differential diagnosis of cough.
Surgery/Anaesthesia:
In patients undergoing major surgery or during anaesthesia with agents that produce
hypotension, ACERYCAL may block angiotensin II formation secondary to compensatory
renin release. The treatment should be discontinued one day prior to the surgery. If
hypotension occurs and is considered to be due to this mechanism, it can be corrected by
volume expansion.
Hyperkalaemia:
Elevations in serum potassium have been observed in some patients treated with ACE
inhibitors, including perindopril. Risk factors for the development of hyperkalaemia include
those with renal insufficiency, worsening of renal function, age (> 70 years), diabetes
mellitus, inter-current events, in particular dehydration, acute cardiac decompensation,
metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g. spironolactone,
eplerenone, triamterene, or amiloride), potassium supplements or potassium-containing salt
substitutes; or those patients taking other drugs associated with increases in serum potassium
(e.g. heparin). The use of potassium supplements, potassium-sparing diuretics, or potassiumcontaining salt substitutes particularly in patients with impaired renal function may lead to a
significant increase in serum potassium. Hyperkalaemia can cause serious, sometimes fatal
arrhythmias. If concomitant use of perindopril and any of the above mentioned agents is
deemed appropriate, they should be used with caution and with frequent monitoring of serum
potassium (see section 4.5).
Diabetic patients:
In diabetic patients treated with oral antidiabetic agents or insulin, glycaemic control should
be closely monitored during the first month of treatment with an ACE inhibitor (see section
4.5).
Linked to amlodipine:
Precautions for use
The safety and efficacy of amlodipine in hypertensive crisis has not been established.
Use in patients with cardiac failure:
Patients with heart failure should be treated with caution.

In a long-term, placebo controlled study in patients with severe heart failure (NYHA class III
and IV) the reported incidence of pulmonary oedema was higher in the amlodipine treated
group than in the placebo group (see section 5.1). Calcium channel blockers, including
amlodipine, should be used with caution in patients with congestive heart failure, as they may
increase the risk of future cardiovascular events and mortality.
Use in patients with impaired hepatic function:
The half-life of amlodipine is prolonged and AUC values are higher in patients with impaired
liver function; dosage recommendations have not been established. Amlodipine should
therefore be initiated at the lower end of the dosing range and caution should be used, both on
initial treatment and when increasing the dose. Slow dose titration and careful monitoring
may be required in patients with severe hepatic impairment.
Use in elderly patients:
In the elderly increase of the dosage should take place with care (see sections 4.2 and 5.2).
Use in renal failure:
Amlodipine may be used in such patients at normal doses. Changes in amlodipine plasma
concentrations are not correlated with degree of renal impairment. Amlodipine is not
dialysable.
Linked to ACERYCAL
All warnings related to each mono-component, as listed above, should apply also to the fixed
combination of ACERYCAL.
Precautions for use
Excipients:
Due to the presence of lactose, patients with rare hereditary problems of galactose intolerance,
glucose-galactose malabsorption, or the Lapp lactase deficiency should not take this
medicinal product.
Interactions
The concomitant use of ACERYCAL with lithium, potassium-sparing diuretics or potassium
supplements, or dantrolene is not recommended (see section 4.5).

4.5

Interaction with other medicinal products and other forms of interaction

Linked to perindopril
Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system
(RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or
aliskiren is associated with a higher frequency of adverse events such as hypotension,
hyperkalaemia and decreased renal function (including acute renal failure) compared to the
use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).
Concomitant use not recommended:
Potassium sparing diuretics, potassium supplements or potassium-containing salt substitutes:
Although serum potassium usually remains within normal limits, hyperkalaemia may occur in
some patients treated with perindopril. Potassium sparing diuretics (e.g. spironolactone,
triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes
may lead to significant increases in serum potassium. Therefore the combination of
perindopril with the above-mentioned drugs is not recommended (see section 4.4). If
concomitant use is indicated because of demonstrated hypokalaemia they should be used with
caution and with frequent monitoring of serum potassium.

Lithium:
Reversible increases in serum lithium concentrations and toxicity (severe neurotoxicity) have
been reported during concurrent use of ACE inhibitors. The combination of perindopril with
lithium is not recommended. If the combination proves necessary, careful monitoring of
serum lithium levels is recommended (see section 4.4).
Estramustine:
Risk of increased adverse effects such as angioneurotic oedema (angioedema).
Concomitant use which requires special care:
Non-steroidal anti-inflammatory medicinal products (NSAIDs) including aspirin ≥ 3 g/day:
When ACE-inhibitors are administered simultaneously with non-steroidal anti-inflammatory
drugs (i.e. acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 inhibitors and
non-selective NSAIDs), attenuation of the antihypertensive effect may occur. Concomitant
use of ACE-inhibitors and NSAIDs may lead to an increased risk of worsening of renal
function, including possible acute renal failure, and an increase in serum potassium,
especially in patients with poor pre-existing renal function. The combination should be
administered with caution, especially in the elderly. Patients should be adequately hydrated
and consideration should be given to monitoring renal function after initiation of concomitant
therapy, and periodically thereafter.
Antidiabetic agents (insulin, hypoglycaemic sulfonamides):
The use of angiotensin converting enzyme inhibitors may increase the hypoglycaemic effect
in diabetics receiving treatment with insulin or with hypoglycaemic sulfonamides. The onset
of hypoglycaemic episodes is very rare (there is probably an improvement in glucose
tolerance with a resulting reduction in insulin requirements).
Concomitant use to be taken into consideration:
Diuretics:
Patients on diuretics, and especially those who are volume and/or salt depleted, may
experience excessive reduction in blood pressure after initiation of therapy with an ACE
inhibitor. The possibility of hypotensive effects can be reduced by discontinuation of the
diuretic, by increasing volume or salt intake prior to initiating therapy with low and
progressive doses of perindopril.
Sympathomimetics:
Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.
Gold:
Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension)
have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate)
and concomitant ACE inhibitor therapy including perindopril.
Linked to amlodipine
Concomitant use not recommended:
Dantrolene (infusion): In animals, lethal ventricular fibrillation and cardiovascular collapse
are observed in association with hyperkalemia after administration of verapamil and
intravenous dantrolene. Due to risk of hyperkalemia, it is recommended that the coadministration of calcium channel blockers such as amlodipine be avoided in patients
susceptible to malignant hyperthermia and in the management of malignant hyperthermia.

Concomitant use which requires special care:
CYP3A4 inducers: There is no data available regarding the effect of CYP3A4 inducers on
amlodipine. The concomitant use of CYP3A4 inducers (e.g., rifampicin, hypericum

perforatum) may give a lower plasma concentration of amlodipine. Amlodipine should be
used with caution together with CYP3A4 inducers.
CYP3A4 inhibitors: Concomitant use of amlodipine with strong or moderate CYP3A4
inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or
clarithromycin, verapamil or diltiazem) may give rise to significant increase in amlodipine
exposure. The clinical translation of these PK variations may be more pronounced in the
elderly. Clinical monitoring and dose adjustment may thus be required.
Concomitant use to be taken into consideration:
The blood pressure lowering effects of amlodipine adds to the blood pressure-lowering
effects of other medicinal products with antihypertensive properties..
Others combinations:
In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin,
digoxin, warfarin or cyclosporin.
Administration of amlodipine with grapefruit or grapefruit juice is not recommended as
bioavailability may be increased in some patients resulting in increased blood pressure
lowering effects.
Linked to ACERYCAL
Concomitant use which requires special care:
Baclofen. Potentiation of antihypertensive effect. Monitoring of blood pressure and renal
function, and dose adaptation of the antihypertensive if necessary.
Concomitant use to be taken into consideration:
. Antihypertensive agents (such as beta-blockers) and vasodilatators:
Concomitant use of these agents may increase the hypotensive effects of perindopril and
amlodipine. Concomitant use with nitroglycerin and other nitrates or other vasodilatators,
may further reduce blood pressure and therefore should be considered with caution.
. Corticosteroids, tetracosactide: reduction in antihypertensive effect (salt and water
retention due to corticosteroids).
. Alpha-blockers (prazosin, alfuzosin, doxazosin, tamsulosin, terazosin): increased
antihypertensive effect and increased risk of orthostatic hypotension.
. Amifostine: may potentiate the antihypertensive effect of amlodipine.
. Tricyclic antidepressants/antipsychotics/anaesthetics: increased antihypertensive effect
and increased risk of orthostatic hypotension.

4.6

Pregnancy and lactation
Given the effects of the individual components in this combination product on
pregnancy and lactation:
ACERYCAL is not recommended during the first trimester of pregnancy.
ACERYCAL is contraindicated during the second and third trimesters of pregnancy.
ACERYCAL is not recommended during lactation. A decision should therefore be
made whether to discontinue nursing or to discontinue ACERYCAL taking account
the importance of this therapy for the mother.
Pregnancy:
Linked to perindopril

The use of ACE inhibitors is not recommended during the first trimester of pregnancy
(see section 4.4). The use of ACE inhibitors is contraindicated during the second and
third trimester of pregnancy (see sections 4.3 and 4.4).
Epidemiological evidence regarding the risk of teratogenicity following exposure to
ACE inhibitors during the first trimester of pregnancy has not been conclusive;
however a small increase in risk cannot be excluded. Unless continued ACE inhibitor
therapy is considered essential, patients planning pregnancy should be changed to
alternative antihypertensive treatments which have an established safety profile for
use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors
should be stopped immediately, and, if appropriate, alternative therapy should be
started.
Exposure to ACE inhibitor therapy during the second and third trimesters is known to
induce human foetotoxicity (decreased renal function, oligohydramnios, skull
ossification retardation) and neonatal toxicity (renal failure, hypotension,
hyperkalaemia) (see section 5.3).
Should exposure to ACE inhibitor have occurred from the second trimester of
pregnancy, ultrasound check of renal function and skull is recommended.
Infants whose mothers have taken ACE inhibitors should be closely observed for
hypotension (see sections 4.3 and 4.4).
Linked to amlodipine
The safety of amlodipine in human pregnancy has not been established.
In animal studies, reproductive toxicity was observed at high doses (see section
5.3).Use in pregnancy is only recommended when there is no safer alternative and
when the disease itself carries greater risk for the mother and foetus.
Lactation:
Linked to perindopril
Because no information is available regarding the use of perindopril during
breastfeeding, perindopril is not recommended and alternative treatments with better
established safety profiles during breast-feeding are preferable, especially while
nursing a newborn or preterm infant.
Linked to amlodipine
It is not known whether amlodipine is excreted in breast milk. A decision on whether
to continue/discontinue breast-feeding or to continue/discontinue therapy with
amlodipine should be made taking into account the benefit of breast-feeding to the
child and the benefit of amlodipine therapy to the mother.
Fertility:
Reversible biochemical changes in the head of spermatozoa have been reported in
some patients treated by calcium channel blockers. Clinical data are insufficient
regarding the potential effect of amlodipine on fertility. In one rat study, adverse
effects were found on male fertility (see section 5.3).

4.7

Effects on ability to drive and use machines

No studies on the effects of ACERYCAL on the ability to drive and use machines
have been performed. Amlodipine can have minor or moderate influence on the
ability to drive and use machines. If patients suffer from dizziness, headache, fatigue,
weariness or nausea, the ability to react may be impaired. Caution is recommended
especially at the start of treatment.

4.8

Undesirable effects

The following undesirable effects have been observed during treatment with perindopril or
amlodipine given separately and ranked under the MedDRA classification by body system
and under the following frequency:

Very common (≥1/10); common (≥1/100 to <1/10) ; uncommon (≥1/1000 to <1/100) ;
rare (≥1/10000 to <1/1000) ; very rare (<1/10000) ; not known (cannot be estimated
from the available data).
MedDRA
System Organ
Class
Blood and the
lynphatic
System
Disorders

Frequency

Undesirable Effects

Amlodipin Perindopr
e
il
Leucopenia/neutropenia (see section 4.4)

Very rare

Very rare

-

Very rare

Very rare

Very rare

Haemolytic anaemia in patients with a congenital
deficiency of G-6PDH (see section 4.4)

-

Very rare

Decrease in haemoglobin and haematocrit

-

Very rare

Agranulocytosis or pancytopenia (see section 4.4)
Thrombocytopenia (see section 4.4)

Immune
System
Disorders

Allergic reactions

Very rare

Uncommo
n

Metabolism
and Nutrition
Disorders

Hyperglycaemia

Very rare

-

-

Not
known

Insomnia

Uncommon

-

Mood changes (including anxiety)

Uncommon Uncommo
n

Depression

Uncommon

-

-

Uncommo
n

Rare

Very rare

Somnolence (especially at the beginning of the treatment)

Common

-

Dizziness (especially at the beginning of the treatment)

Common

Common

Headache (especially at the beginning of the treatment)

Common

Common

Dysgeusia

Uncommon

Common

Tremor

Uncommon

-

Hypoesthaesia

Uncommon

-

Paresthaesia

Uncommon

Common

Syncope

Uncommon

-

Hypertonia

Very rare

-

Peripheral neuropathy

Very rare

-

Psychiatric
disorders

Hypoglycaemia (see sections 4.4 and 4.5)

Sleep disturbances
Confusion
Nervous
System
disorders

MedDRA

Undesirable Effects

System Organ
Class

Amlodipin Perindopr
e
il
Vertigo

-

Common

Uncommon

Common

Uncommon

Common

Common

-

-

Very rare

Myocardial infarction, possibly secondary to excessive
hypotension in high risk patients (see section 4.4)

Very rare

Very rare

Arrhythmia (including bradycardia, ventricular tachycardia
and atrial fibrillation)

Very rare

Very rare

Flushing

Common

-

Uncommon

Common

-

Very rare

Vasculitis

Very Rare

Not
known

Dyspnoea

Uncommon

Common

Rhinitis

Uncommon

Very rare

Cough

Very rare

Common

Bronchospasm

-

Uncommo
n

Eosinophilic pneumonia

-

Very rare

Gingival hyperplasia

Very rare

-

Abdominal pain, nausea

Common

Common

Vomiting

Uncommon

Common

Dyspepsia

Uncommon

Common

Altered bowel habits

Uncommon

-

Dry mouth

Uncommon Uncommo
n

Diarrhoea, constipation

Uncommon

Common

Pancreatitis

Very rare

Very rare

Gastritis

Very rare

-

Very rare

-

-

Very rare

Hepatic enzymes increased (mostly consistent with
cholestasis)

Very rare

-

Quincke’s oedema

Very rare

-

Angioedema of face, extremities, lips, mucous membranes,
tongue, glottis and/or larynx (see section 4.4)

Very rare

Uncommo
n

Eye Disorders Visual disturbances (including diplopia)
Ear and
labyrinth
disorders

Tinnitus

Cardiac
Disorders

Palpitations

Vascular
Disorders

Angina pectoris

Hypotension (and effects related to hypotension)
Stroke possibly secondary to excessive hypotension in
high-risk patients (see section 4.4)

Respiratory,
Thoracic and
Mediastinal
Disorders

Gastrointestinal
Disorders

Hepato-biliary Hepatitis, jaundice
Disorders
Hepatitis either cytolytic or cholestatic (see section 4.4)

Skin and
Subcutaneous

Frequency

MedDRA

Undesirable Effects

Frequency

System Organ
Class
Tissue
Erythema multiform
Disorders
Alopecia

Amlodipin Perindopr
e
il
Very rare

Very rare

Uncommon

-

Purpura

Uncommon

-

Skin discoloration

Uncommon

-

Hyperhidrosis

Uncommon Uncommo
n

Pruritus

Uncommon

Common

Rash, exanthema

Uncommon

Common

Urticaria

Very rare

Uncommo
n

Stevens-Johnson Syndrome

Very rare

-

Exfoliative dermatitis

Very rare

-

Photosensitivity

Very rare

-

Common

-

Uncommon

-

Uncommon

Common

Uncommon

-

Uncommon

-

Renal impairment

-

Uncommo
n

Acute renal failure

-

Very rare

Musculoskelet Ankle swelling
al And
Arthralgia, myalgia
Connective
Tissue
Muscle cramps
Disorders
Back pain
Renal and
Urinary
Disorders

Micturition disorder, nocturia, increased urinary frequency

Reproductive
System and
Breast
Disorders

Impotence

Uncommon Uncommo
n

Gynaecomastia

Uncommon

-

General
Disorders and
Administratio
n Site
Condition

Oedema

Common

-

Fatigue

Common

-

Chest pain

Uncommon

-

Asthenia

Uncommon

Common

Pain

Uncommon

-

Malaise

Uncommon

-

Weight increase, weight decrease

Uncommon

-

-

Rare

-

Not known

Investigations

Serum bilirubin and liver enzymes elevation
Increases in blood urea and
hyperkalaemia (see section 4.4)

serum

creatinine,

Additional information linked to amlodipine
Exceptional cases of extrapyramidal syndrome have been reported with calcium
channel blockers.

4.9

Overdose

There is no information on overdosage with ACERYCAL in humans.
For amlodipine, experience with intentional overdose in humans is limited.
Symptoms: available data suggest that gross overdosage could result in excessive
peripheral vasodilatation and possibly reflex tachycardia. Marked and probably
prolonged systemic hypotension up to and including shock with fatal outcome have
been reported.
Treatment: clinically significant hypotension due to amlodipine overdosage calls for
active cardiovascular support including frequent monitoring of cardiac and respiratory
function, elevation of extremities and attention to circulating fluid volume and urine
output.
A vasoconstrictor may be helpful in restoring vascular tone and blood pressure,
provided that there is no contraindication to its use. Intravenous calcium gluconate
may be beneficial in reversing the effects of calcium channel blockade.
Gastric lavage may be worthwhile in some cases. In healthy volunteers the use of
charcoal up to 2 hours after administration of amlodipine 10 mg has been shown to
reduce the absorption rate of amlodipine.
Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.
For perindopril, limited data are available for overdosage in humans. Symptoms
associated with the overdosage of ACE inhibitors may include hypotension,
circulatory shock, electrolyte disturbances, renal failure, hyperventilation,
tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough.
The recommended treatment of overdosage is intravenous infusion of normal saline
solution. If hypotension occurs, the patient should be placed in the shock position. If
available, treatment with angiotensin II infusion and/or intravenous catecholamines
may also be considered. Perindopril can be removed from the systemic circulation by
haemodialysis (see section 4.4). Pacemaker therapy is indicated for treatment-resistant
bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be
monitored continuously.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: ACE inhibitors and calcium channel blockers, ATC code:
C09BB04.
Perindopril:
Perindopril is an inhibitor of the enzyme that converts angiotensin I into angiotensin II
(Angiotensin Converting Enzyme ACE). The converting enzyme, or kinase, is an
exopeptidase that allows conversion of angiotensin I into the vasoconstrictor angiotensin II as

well as causing the degradation of the vasodilator bradykinin into an inactive heptapeptide.
Inhibition of ACE results in a reduction of angiotensin II in the plasma, which leads to
increased plasma renin activity (by inhibition of the negative feedback of renin release) and
reduced secretion of aldosterone. Since ACE inactivates bradykinin, inhibition of ACE also
results in an increased activity of circulating and local kallikrein-kinin systems (and thus also
activation of the prostaglandin system). It is possible that this mechanism contributes to the
blood pressure-lowering action of ACE inhibitors and is partially responsible for certain of
their side effects (e.g. cough).
Perindopril acts through its active metabolite, perindoprilat. The other metabolites show no
inhibition of ACE activity in vitro.
Hypertension:
Perindopril is active in all grades of hypertension: mild, moderate, severe ; a reduction in
systolic and diastolic blood pressures in both supine and standing positions is observed.
Perindopril reduces peripheral vascular resistance, leading to blood pressure reduction. As a
consequence, peripheral blood flow increases, with no effect on heart rate.
Renal blood flow increases as a rule, while the glomerular filtration rate (GFR) is usually
unchanged.
The antihypertensive activity is maximal between 4 and 6 hours after a single dose and is
sustained for at least 24 hours: trough effects are about 87-100 % of peak effects.
The decrease in blood pressure occurs rapidly. In responding patients, normalisation is
achieved within a month and persists without the occurrence of tachyphylaxis.
Discontinuation of treatment does not lead to a rebound effect.
Perindopril reduces left ventricular hypertrophy.
In man, perindopril has been confirmed to demonstrate vasodilatory properties. It improves
large artery elasticity and decreases the media:lumen ratio of small arteries.
Patients with stable coronary artery disease:
The EUROPA study was a multicentre, international, randomised, double-blind, placebocontrolled clinical trial lasting 4 years.
Twelve thousand two hundred and eighteen (12218) patients aged over 18 were randomised
to 8 mg perindopril tert-butylamine (equivalent to 10 mg perindopril arginine) (n=6110) or
placebo (n=6108).
The trial population had evidence of coronary artery disease with no evidence of clinical signs
of heart failure. Overall, 90% of the patients had a previous myocardial infarction and/or a
previous coronary revascularisation. Most of the patients received the study medication on top
of conventional therapy including platelet inhibitors, lipid lowering agents and beta-blockers.
The main efficacy criterion was the composite of cardiovascular mortality, non fatal
myocardial infarction and/or cardiac arrest with successful resuscitation. The treatment with 8
mg perindopril tert-butylamine (equivalent to 10 mg perindopril arginine) once daily resulted
in a significant absolute reduction in the primary endpoint of 1.9% (relative risk reduction of
20%, 95%CI [9.4; 28.6] – p<0.001).
In patients with a history of myocardial infarction and/or revascularisation, an absolute
reduction of 2.2% corresponding to a RRR of 22.4% (95%CI [12.0; 31.6] – p<0.001) in the
primary endpoint was observed by comparison to placebo.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) clinical trial data:
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in
combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans
Affairs Nephropathy in Diabetes)) have examined the use of combination of an ACE-inhibitor
with an angiotensin II receptor blocker.
ONTARGET was a study conducted in patients with a history of cardiovascular or
cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ

damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic
nephropathy.
These studies have shown no significant beneficial effect on renal and/or cardiovascular
outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or
hypotension as compared to monotherapy was observed.
Given their similar pharmacodynamic properties, these results are also relevant for other
ACE-inhibitors and angiotensin II receptor blockers.
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used
concomitantly in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease
Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of
an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes
mellitus and chronic kidney disease, cardiovascular disease, or both. The study was
terminated early because of an increased risk of adverse outcomes. Cardiovascular death and
stroke were both numerically more frequent in the aliskiren group than in the placebo group
and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and
renal dysfunction) were more frequently reported in the aliskiren group than in the placebo
group.

Amlodipine:
Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (slow channel
blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into
cardiac and vascular smooth muscle.
The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect
on vascular smooth muscle. The precise mechanism by which amlodipine relieves angina has
not been fully determined but amlodipine reduces total ischaemic burden by the following
two actions:
- Amlodipine dilates peripheral arterioles and thus, reduces the total peripheral resistance
(afterload) against which the heart works. Since the heart rate remains stable, this unloading
of the heart reduces myocardial energy consumption and oxygen requirements.
- The mechanism of action of amlodipine also probably involves dilatation of the main
coronary arteries and coronary arterioles, both in normal and ischaemic regions. This
dilatation increases myocardial oxygen delivery in patients with coronary artery spasm
(Prinzmetal's or variant angina).
In patients with hypertension, once daily dosing provides clinically significant reductions of
blood pressure in both the supine and standing positions throughout the 24-hour interval. Due
to the slow onset of action, acute hypotension is not a feature of amlodipine administration.
In patients with angina, once daily administration of amlodipine increases total exercise time,
time to angina onset, and time to 1mm ST segment depression, and decreases both angina
attack frequency and glyceryl trinitrate tablet consumption.
Amlodipine has not been associated with any adverse metabolic effects or changes in plasma
lipids and is suitable for use in patients with asthma, diabetes, and gout.
Patients with coronary artery disease (CAD):
The effectiveness of amlodipine in preventing clinical events in patients with coronary artery
disease (CAD) has been evaluated in an independent, multi-center, randomized, doubleblind, placebo-controlled study of 1997 patients; Comparison of Amlodipine vs. Enalapril to
Limit Occurrences of Thrombosis (CAMELOT). Of these patients, 663 were treated with
amlodipine 5-10 mg, 673 patients were treated with enalapril 10-20 mg, and 655 patients were
treated with placebo, in addition to standard care of statins, beta-blockers, diuretics and
aspirin, for 2 years. The key efficacy results are presented in Table 1. The results indicate that

amlodipine treatment was associated with fewer hospitalizations for angina and
revascularization procedures in patients with CAD.

Table 1. Incidence of significant clinical outcomes for CAMELOT
Cardiovascular event rates, No. (%)
Outcomes

Amlodipine vs. placebo

Amlodipine

Placebo

Enalapril

Hazard Ratio
(95% CI)

P Value

110 (16.6)

151 (23.1)

136 (20.2)

0.69 (0.54-0.88)

.003

78 (11.8)

103 (15.7)

95 (14.1)

0.73 (0.54-0.98)

.03

51 (7.7)

84 (12.8)

86 (12.8)

0.58 (0.41-0.82)

.002

14 (2.1)

19 (2.9)

11 (1.6)

0.73 (0.37-1.46)

.37

6 (0.9)

12 (1.8)

8 (1.2)

0.50 (0.19-1.32)

.15

5 (0.8)

2 (0.3)

5 (0.7)

2.46 (0.48-12.7)

.27

3 (0.5)

5 (0.8)

4 (0.6)

0.59 (0.14-2.47)

.46

0

4 (0.6)

1 (0.1)

NA

.04

5 (0.8)

2 (0.3)

8 (1.2)

2.6 (0.50-13.4)

.24

Primary Endpoint
Adverse
events

cardiovascular

Individual Components
Coronary
revascularization
Hospitalization for angina
Nonfatal MI
Stroke or TIA
Cardiovascular death
Hospitalization for CHF
Resuscitated
arrest

cardiac

New-onset
peripheral
vascular disease
Abbreviations: CHF, congestive heart failure; CI, confidence interval; MI, myocardial
infarction; TIA, transient ischemic attack.
Use in patients with heart failure:
Haemodynamic studies and exercise based controlled clinical trials in NYHA Class II-IV
heart failure patients have shown that amlodipine did not lead to clinical deterioration as
measured by exercise tolerance, left ventricular ejection fraction and clinical
symptomatology.
A placebo controlled study (PRAISE) designed to evaluate patients in NYHA Class III-IV
heart failure receiving digoxin, diuretics and ACE inhibitors has shown that amlodipine did
not lead to an increase in risk of mortality or combined mortality and morbidity with heart
failure.
In a follow-up, long term, placebo controlled study (PRAISE-2) of amlodipine in patients
with NYHA III and IV heart failure without clinical symptoms or objective findings
suggestive or underlying ischaemic disease, on stable doses of ACE inhibitors, digitalis, and
diuretics, amlodipine had no effect on total cardiovascular mortality. In this same population
amlodipine was associated with increased reports of pulmonary oedema.
Treatment to prevent heart attack trial (ALLHAT):
A randomized double-blind morbidity-mortality study called the Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT) was performed to compare
newer drug therapies: amlodipine 2.5-10 mg/d (calcium channel blocker) or lisinopril 10-40
mg/d (ACE-inhibitor) as first-line therapies to that of the thiazide-diuretic, chlorthalidone
12.5-25 mg/d in mild to moderate hypertension.

A total of 33,357 hypertensive patients aged 55 or older were randomized and followed for a
mean of 4.9 years. The patients had at least one additional CHD risk factor, including:
previous myocardial infarction or stroke > 6 months prior to enrolment or documentation of
other atherosclerotic CVD (overall 51.5%), type 2 diabetes (36.1%), HDL-C < 35 mg/dL
(11.6%), left ventricular hypertrophy diagnosed by electrocardiogram or echocardiography
(20.9%), current cigarette smoking (21.9%).
The primary endpoint was a composite of fatal CHD or non-fatal myocardial infarction. There
was no significant difference in the primary endpoint between amlodipine-based therapy and
chlorthalidone-based therapy: RR 0.98 (95% CI(0.90-1.07) p=0.65). Among secondary
endpoints, the incidence of heart failure (component of a composite combined cardiovascular
endpoint) was significantly higher in the amlodipine group as compared to the chlorthalidone
group (10.2% vs 7.7%, RR 1.38, (95% CI [1.25-1.52] p<0.001)). However, there was no
significant difference in all-cause mortality between amlodipine-based therapy and
chlorthalidone-based therapy, RR 0.96 (95% CI [0.89-1.02] p=0.20).

5.2

Pharmacokinetic properties

The rate and extent of absorption of perindopril and amlodipine from ACERYCAL are not
significantly different, respectively, from the rate and extent of absorption of perindopril and
amlodipine from individual tablet formulations.

Perindopril:
After oral administration, the absorption of perindopril is rapid and the peak
concentration is achieved within 1 hour. The plasma half-life of perindopril is equal to
1 hour.
Perindopril is a pro-drug. Twenty seven percent of the administered perindopril dose
reaches the bloodstream as the active metabolite perindoprilat. In addition to active
perindoprilat, perindopril yields five metabolites, all inactive. The peak plasma
concentration of perindoprilat is achieved within 3 to 4 hours.
As ingestion of food decreases conversion to perindoprilat, hence bioavailability,
perindopril arginine should be administered orally in a single daily dose in the
morning before a meal.
It has been demonstrated a linear relationship between the dose of perindopril and its
plasma exposure.
The volume of distribution is approximately 0.2 l/kg for unbound perindoprilat.
Protein binding of perindoprilat to plasma proteins is 20%, principally to angiotensin
converting enzyme, but is concentration-dependent. Perindoprilat is eliminated in the
urine and the terminal half-life of the unbound fraction is approximately 17 hours,
resulting in steady-state within 4 days.
Elimination of perindoprilat is decreased in the elderly, and also in patients with heart
or renal failure (see section 4.2). Therefore, the usual medical follow-up will include
frequent monitoring of creatinine and potassium.
Dialysis clearance of perindoprilat is equal to 70 ml/min.
Perindopril kinetics are modified in patients with cirrhosis: hepatic clearance of the
parent molecule is reduced by half. However, the quantity of perindoprilat formed is
not reduced and therefore no dosage adjustment is required (see sections 4.2 and 4.4).
Amlodipine:

After oral administration of therapeutic doses, amlodipine is well absorbed with peak
blood levels between 6-12 hours post dose. Absolute bioavailability has been
estimated to be between 64 and 80%. The volume of distribution is approximately 21
l/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine
is bound to plasma proteins.
The bioavailability of amlodipine is not affected by food intake.
The terminal plasma elimination half-life is about 35-50 hours and is consistent with
once daily dosing. Amlodipine is extensively metabolised by the liver to inactive
metabolites with 10% of the parent compound and 60% of metabolites excreted in the
urine.
Use in the elderly: the time to reach peak plasma concentrations of amlodipine is similar in
elderly and younger subjects. Amlodipine clearance tends to be decreased with resulting
increases in AUC and elimination half-life in elderly patients. Increases in AUC and
elimination half-life in patients with congestive heart failure were as expected for the patient
age group studied.
Use in patients with impaired hepatic function: Very limited clinical data are available
regarding amlodipine administration in patients with hepatic impairment. Patients with
hepatic insufficiency have decreased clearance of amlodipine resulting in a longer half-life
and an increase in AUC of approximately 40-60%.

5.3

Preclinical safety data

Perindopril:
In the chronic oral toxicity studies (rats and monkeys), the target organ is the kidney, with
reversible damage.

No mutagenicity has been observed in in vitro or in vivo studies.
Reproduction toxicology studies (rats, mice, rabbits and monkeys) showed no sign of
embryotoxicity or teratogenicity. However, angiotensin converting enzyme inhibitors,
as a class, have been shown to induce adverse effects on late foetal development,
resulting in foetal death and congenital effects in rodents and rabbits: renal lesions and
an increase in peri- and postnatal mortality have been observed.
No carcinogenicity has been observed in long term studies in rats and mice.

Amlodipine:
Reproductive studies in rats and mice have shown delayed date of delivery, prolonged
duration of labour and decreased pup survival at dosages approximately 50 times
greater than the maximum recommended dosage for humans based on mg/kg.
There was no effect on the fertility of rats treated with amlodipine (males for 64 days
and females 14 days prior to mating) at doses up to 10 mg/kg/day (8 times* the
maximum recommended human dose of 10 mg on a mg/m2 basis). In another rat
study in which male rats were treated with amlodipine besilate for 30 days at a dose
comparable with the human dose based on mg/kg, decreased plasma folliclestimulating hormone and testosterone were found as well as decreases in sperm
density and in the number of mature spermatids and Sertoli cells.
Rats and mice treated with amlodipine in the diet for two years, at concentrations
calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg/kg/day showed no
evidence of carcinogenicity. The highest dose (for mice, similar to, and for rats twice*

the maximum recommended clinical dose of 10 mg on a mg/m2 basis) was close to
the maximum tolerated dose for mice but not for rats.
Mutagenicity studies revealed no drug related effects at either the gene or
chromosome levels.
* Based on patient weight of 50 kg

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Lactose monohydrate

Cellulose, microcrystalline (E460)
Silica, colloidal anhydrous (E551)
Magnesium stearate (E470B)
6.2

Incompatibilities
Not applicable

6.3.

Shelf life
3 years

6.4

Special precautions for storage
Keep the container tightly closed in order to protect from moisture. Store in the
original package.

6.5

Nature and contents of container
5, 7, 10, 14, 20, 28, 30 or 50 tablets in polypropylene container equipped with
a low density polyethylene flow reducer and a low density polyethylene
stopper containing a desiccant gel.
Box of 1 container of 5, 7, 10, 14, 20, 28, 30 or 50 tablets.
Box of 2 containers of 28, 30 or 50 tablets.
Box of 3 containers of 30 tablets.
Box of 4 containers of 30 tablets.
Box of 10 containers of 50 tablets.
Not all pack sizes may be marketed

6.6

Special precautions for disposal
No special requirements.

7

MARKETING AUTHORISATION HOLDER

Les Laboratoires Servier
50, rue Carnot
92284 Suresnes cedex
France

8

MARKETING AUTHORISATION NUMBER(S)
PL 05815/0059

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
29/05/2009

10

DATE OF REVISION OF THE TEXT
22/02/2015

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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